Matrix metalloproteinase-2 & progressive cardiac fibrosi

描述（由申请人提供）： 作为对损伤的反应的心脏的持续功能障碍性重塑代表导致心室衰竭和死亡的最终共同途径。心脏的心脏成纤维细胞成分的增殖能力和细胞外基质合成谱的变化是这些事件的主要原因。心脏成纤维细胞表型的这些变化是由衰竭心脏内通常存在的条件和肽因子驱动的，包括组织缺氧和促纤维化肽（如血管紧张素II、内皮素-1和白细胞介素-1）的释放增强。心室重塑也与几种基质金属蛋白酶的合成增强有关，其中MMP-2（明胶酶A）可能具有核心重要性。该提议的主要假设是，响应于缺血性损伤和促纤维化肽的明胶酶A的合成增强直接驱动导致进行性心力衰竭的心脏成纤维细胞表型的功能障碍性变化。该计划将研究明胶酶A对血管紧张素II、内皮素-1和白细胞介素-1的转录调节，以确定关键的增强子元件和转录因子， 这种酶在心脏中的高水平合成。这些转录调控的有效性 将使用在特异性增强子元件中含有确定突变的转基因明胶酶A小鼠在基因组背景中直接测试机制。最后，明胶酶A作为单独药剂诱导功能障碍性心室重构的能力将使用心脏中的靶向基因表达在体内进行测试。这些研究应提供关键的洞察力的作用，一个特定的基质金属蛋白酶在心脏对损伤的反应，并可能提供病理生理基础的发展，这种致残性疾病的新形式的治疗。

DESCRIPTION (provided by applicant): Persistent dysfunctional remodeling of the heart as a response to injury represents a final common pathway resulting in ventricular failure and death. Changes in the proliferative capacity and extracellular matrix synthetic profile of the cardiac fibroblast component of the heart are primarily responsible for these events. These changes in the cardiac fibroblast phenotype are driven by conditions and peptide factors commonly present within the failing heart, including tissue hypoxia and enhanced release of pro-fibrotic peptides, such as angiotensin II, endothelin-1 and Interleukin-1 . Ventricular remodeling is also associated with enhanced synthesis of several matrix metalloproteinases, of which MMP-2 (gelatinase A) may be of central importance. The primary hypothesis of this proposal is that enhanced synthesis of gelatinase A in response to ischemic injury and pro-fibrotic peptides directly drives the dysfunctional changes in cardiac fibroblast phenotypes responsible for progressive cardiac failure. This proposal will examine the transcriptional regulation of gelatinase A in response to angiotensin II, endothelin-1 and Interleukin-1 to define critical enhancer elements and transcription factors that drive high level synthesis of this enzyme in the heart. The validity of these transcriptional regulatory mechanisms will be directly tested in a genomic context using transgenic gelatinase A mice containing defined mutations in specific enhancer elements. Finally, the ability of gelatinase A as an individual agent to induce dysfunctional ventricular remodeling will be tested in vivo using targeted gene expression in the heart. These studies should provide key insights into the role of a specific matrix metalloproteinase in the cardiac response to injury and could provide the pathophysiologic basis for the development of new forms of therapy for this disabling condition.